Approximately 30,000 people in the United States are diagnosed each year with pancreatic cancer (PanCa). Over 90% of these will die of the disease making PanCa one of the most devastating human malignancies. The current 5-year survival rate of less than 4% has changed little in the last 20 years despite improvements in therapy including the introduction of chemotherapeutic agents such as gemcitabine (Gemzar). Thus, there is an urgent need for an improved therapy for the 80% of PanCa that are unresectable and/or metastatic. Progress has been made toward delineating the genetic errors contributing to PanCa thus opening up new approaches to therapy. The HER-2 proto-oncogene is overexpressed in 60-80% of PanCa. Down modulation of HER-2 protein via the antisense (AS) approach can inhibit PanCa cell growth in vitro and in vivo. However, until now efficient systemic AS oligonucleotide (ODN) delivery has been problematic. We have developed a tumor-targeted liposomal AS ODN complex using an anti-transferrin receptor single-chain antibody fragment (TfRscFv) as the targeting entity. This immunoliposome complex can systemically deliver AS HER-2 (ODN) preferentially to PanCa tumors regardless of their HER-2 levels. In the Phase I work we optimized the complex and have shown systemic targeting of this complex specifically to PanCa tumor, in both primary and an orthotopic metastasis model and that the resultant down modulation of HER-2 leads to an increased sensitization of PanCa tumor cells to Gemzar in vitro and (in preliminary studies) in vivo. In this Phase II application we propose to test the anti-tumor efficacy of the optimized TfRscFv-liposome-AS HER-2 complex in subcutaneous xenograft and orthotopic metastasis models of PanCa. Other studies prerequisite to clinical trials, such as biodistribution and LD10, will also be undertaken and we will examine the use of a marker of apoptosis as a less invasive means to assess efficacy. In addition we will also begin to explore the organization and structure of the TfRscFv-liposome-AS HER-2 complex. Our ultimate goal is to develop this systemic, tumor-targeting immunoliposome AS HER-2 complex for use in combination with Gemzar as a novel and effective treatment modality for PanCa. This dual targeting (molecular and tumor) design has the potential to significantly expand the therapeutic utility of the anti-HER-2 strategy.